Damage to the orbitofrontal cortex (OFC) may contribute to persistent craving and compulsive drug seeking in former drug users. Consistent with this, lOFC lesions induced prior to self-administration training potentiate context-induced cocaine seeking in a rat model of drug relapse. The guiding hypothesis of this proposal is that prolonged loss of output from the lOFC enhances context-induced motivation for cocaine by eliciting compensatory neuroadaptations in other elements of the brain circuitry of drug relapse. Overall, this proposal will utilize the contextual extinction-reinstatement model of drug relapse in which rats are trained to self-administer cocaine in a distinct environmental context, followed by extinction training in a different context. Context-induced motivation for cocaine is then assessed in the cocaine-paired context in the absence of cocaine reinforcement. Specific Aim 1 will test the hypothesis that pre-training lOFC lesions prompt enhanced context-induced motivation for cocaine and associated compensatory neuroadaptations in immediate-early gene (lEG) expression in elements of the mesocorticolimbic relapse circuitry. To this end, we will administer lesions of the lOFC prior to cocaine self-administration training and then use in situ hybridization histochemistry to assess mRNA expression of the activity-dependent lEG zinc finger 268 (zif268) and brain-derived neurotrophic factor (BDNF), following reinstatement testing in the cocaine-paired context. Specific Aim 2 will test the hypothesis that reversing lOFC lesion-induced increases in zif268 and BDNF expression in critical brain regions will abolish lOFC lesion-induced enhancement in context-induced motivation for cocaine. To assess whether lOFC lesion-induced increases in lEG expression are necessary for enhanced context-induced reinstatement, immediately before reinstatement testing, rats with pre-training lOFC lesions will receive zif268 or BDNF antisense oligodeoxynucleotide infusions into brain regions that exhibit the most robust elevation in zif268 or BDNF expression in the lOFC lesion vs. sham groups. Public Health Relevance: Cocaine addiction is a prominent health and social issue in the United States, with about 1.6 million individual classified as cocaine dependent (2007 NSDUH, NIDA). OFC damage in cocaine addicts has been theorized to promote addictive behavior and the proposed project utilizes a rodent model of drug relapse to explore the cellular and functional neuroanatomical mechanisms of this phenomenon. Understanding the neural mechanisms underlying of OFC lesion-induced loss of control in drug seeking may offer critical insight for addiction treatment development.